title: DNA-methylation profiling distinguishes malignant melanomas from benign nevi.
abstract: DNA methylation, an epigenetic alteration typically occurring early in cancer development, could aid in the molecular diagnosis of melanoma. We determined technical feasibility for high-throughput DNA-methylation array-based profiling using formalin-fixed paraffin-embedded tissues for selection of candidate DNA-methylation differences between melanomas and nevi. Promoter methylation was evaluated in 27 common benign nevi and 22 primary invasive melanomas using a 1505 CpG site microarray. Unsupervised hierarchical clustering distinguished melanomas from nevi; 26 CpG sites in 22 genes were identified with significantly different methylation levels between melanomas and nevi after adjustment for age, sex, and multiple comparisons and with β-value differences of ≥ 0.2. Prediction analysis for microarrays identified 12 CpG loci that were highly predictive of melanoma, with area under the receiver operating characteristic curves of > 0.95. Of our panel of 22 genes, 14 were statistically significant in an independent sample set of 29 nevi (including dysplastic nevi) and 25 primary invasive melanomas after adjustment for age, sex, and multiple comparisons. This first report of a DNA-methylation signature discriminating melanomas from nevi indicates that DNA methylation appears promising as an additional tool for enhancing melanoma diagnosis.
authors.affiliation: Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC, USA. kconway@med.unc.edu
authors.forename: Kathleen
authors.initials: K
authors.lastname: Conway
authors.forename: Sharon N
authors.initials: SN
authors.lastname: Edmiston
authors.forename: Zakaria S
authors.initials: ZS
authors.lastname: Khondker
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Groben
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.forename: Haitao
authors.initials: H
authors.lastname: Chu
authors.forename: Pei Fen
authors.initials: PF
authors.lastname: Kuan
authors.forename: Honglin
authors.initials: H
authors.lastname: Hao
authors.forename: Craig
authors.initials: C
authors.lastname: Carson
authors.forename: Marianne
authors.initials: M
authors.lastname: Berwick
authors.forename: David W
authors.initials: DW
authors.lastname: Olilla
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Thomas
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D006801:Humans; D008545:Melanoma / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D009506:Nevus / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D012372:ROC Curve; D012878:Skin Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor